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Parkinsonism and Related Disorders 31 (2016) 3e13

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Parkinsonism and Related Disorders


journal homepage: www.elsevier.com/locate/parkreldis

Editor's Comment: In this excellent review manuscript, Smulders et al present an overview of gait abnormalities in Parkinson disease (PD)
patients and the effects of dopaminergic medical therapies on different components of gait impairment in PD. They state that there is
substantial evidence for improvement of some gait features in PD patients with levodopa and levodopa-enhancing therapies. There is also a
possibility that the cholinesterase inhibitors might improve some gait dysfunction characteristics as well.

Zbigniew K. Wszolek, Editor-in-Chief, Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.

Review article

Pharmacological treatment in Parkinson's disease: Effects on gait


Katrijn Smulders a, *, Marian L. Dale a, Patricia Carlson-Kuhta a, John G. Nutt a,
Fay B. Horak a, b
a
Oregon Health & Science University, Department of Neurology, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, United States
b
VA Portland Health Care Systems, Department of Research, 3710 SW US Veteran Hospital Road, Portland, OR, 97230, United States

a r t i c l e i n f o a b s t r a c t

Article history: Gait impairments are a hallmark of Parkinson's disease (PD), both as early symptom and an important
Received 16 June 2016 cause of disability later in the disease course. Although levodopa has been shown to improve gait speed
Received in revised form and step length, the effect of dopamine replacement therapy on other aspects of gait is less well un-
8 July 2016
derstood. In fact, falls are not reduced and some aspects of postural instability during gait are unre-
Accepted 14 July 2016
sponsive to dopaminergic treatment. Moreover, many medications other than dopaminergic agents, can
benet or impair gait in people with PD. We review the effects of pharmacological interventions used in
Keywords:
PD on gait, discriminating, whenever possible, among effects on four components of everyday mobility:
Gait
Dopamine
straight walking, gait initiation, turning, gait adaptability. Additionally, we summarize the effects on
Acetylcholine freezing of gait. There is substantial evidence for improvement of spatial characteristics of simple,
Turning straight-ahead gait with levodopa and levodopa-enhancing drugs. Recent work suggests that drugs
Falls aiming to enhance the acetylcholine system might improve gait stability measures. There is a lack of
well-designed studies to evaluate effects on more complex, but highly relevant walking abilities such as
turning and making exible adjustments to gait. Finally, paucity in the literature exists on detrimental
effects of drugs used in PD that are known to worsen gait and postural stability in the elderly population.
2016 Elsevier Ltd. All rights reserved.

1. Introduction therapies on control of gait are even less well studied than levodopa.
Other therapies include adjunctive therapies to levodopa, as well as
Gait difculty is a highly disabling symptom of Parkinson's dis- medications that are used to treat cognitive decits or other co-
ease. In the earliest stages of the disease bradykinesia is reected in morbidities. The aim of this review is to give an overview of the
smaller arm swing, slower turns and reductions in step length [1e4]. current knowledge on the effects of different pharmacological in-
With disease progression, gait becomes more unstable, freezing of terventions on gait. We will not limit this to medications that improve
gait (FoG) episodes occur, and falls are frequently reported [5e7]. gait, but also discuss medication associated with deterioration of gait
These gait decits severely impact mobility and quality of life [8,9]. or increased fall risk. Where possible, four components of gait will be
Although the main therapies for PD, dopamine restoring agents, are discriminated: straight walking, gait initiation, turning, gait adapt-
helpful for bradykinesia, rigidity, and tremor, they have a mixed effect ability. In addition we will discuss pharmacological effects on FoG.
on gait and postural instability. The effects of other pharmacological
1.1. Gait in healthy individuals
* Corresponding author. Oregon Health & Science University, Department of
Neurology, OP32, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, United
States. Gait has a multitude of components, each of which requires
E-mail address: katrijn.smulders@gmail.com (K. Smulders). varying degrees of cognitive, and therefore, cortical control (Fig. 1).

http://dx.doi.org/10.1016/j.parkreldis.2016.07.006
1353-8020/ 2016 Elsevier Ltd. All rights reserved.
4 K. Smulders et al. / Parkinsonism and Related Disorders 31 (2016) 3e13

Fig. 1. Different components of walking in everyday life and related objective outcome measures. A. Straight walking can be characterized by spatial and temporal variables of the
stride (left-left heel strike) and step (left-right heel strike), motion of the arm and trunk, gait speed and cadence (steps per minute). Stability of gait can be characterized by step-to-
step or stride-to-stride (depicted by each colored block) variability of stride length. Low variability indicates that the stride length or stride time is relatively constant, whereas high
variability indicates large changes of stride length or stride time between strides. Double support time is dened as the percentage of the gait cycle during which both feet are on
the ground; i.e. between heel strike of one foot and toe-off of the other foot. B. Gait initiation can be characterized by the anticipatory postural adjustments (APA) that precedes the
onset of the rst step. The CoP rst moves posteriorly and toward the stepping foot in order to accelerate the CoM forward and toward the stance foot. Execution of the rst step is
described in terms of step length and step duration. C. Turning during walking consists of a sequence of rotations of eyes-head-trunk-feet. The turning velocity and duration are
most commonly quantied using the trunk motion. Another common outcome measure is number of steps needed to complete the turn. D. Gait adaptability, here limited to
obstacle avoidance, can be quantied as the success rate in preventing collision with the obstacle, the clearance of the crossing foot, foot placement, time spent on one leg and total
duration of obstacle crossing. Stability during obstacle crossing can be measured by quantifying CoM movement.
* Variables that are not affected in PD as compared to their healthy peers.
Abbreviations: CoP: center of pressure; CoM: center of mass.

The rst, and least cognitive (or most automatic) component, in which the subjects walk while stepping over or around obstacles.
straight walking over a at surface, requires only minimal attention Typical outcome measures of gait adaptability using obstacle avoid-
in healthy young adults [10,11]. The main parameters for straight ance are success rates, clearance of the obstacles (distance between
walking reect speed (gait speed, step or stride time, cadence), foot and obstacle), and stability during obstacle crossing.
amplitude (step or stride length, arm swing), regularity of move-
ment (step-to-step variability, step width variability), and control 2. Gait decits in Parkinson's disease
of balance (step width, trunk motion).
A second component, initiation of gait, involves more cortical 2.1. Straight walking
control than straight walking as it generates goal-directed move-
ments. Gait initiation consists of a postural weight shift forward The hallmark motor symptom of PD, bradykinesia, is reected in
and toward the stance leg in order to unload the stepping leg, gait. The slow gait associated with PD is predominantly due to short
which is dened as the anticipatory postural adjustment (APA). steps, rather than slow cadence [19,20]. Short steps are caused by
Following the APA, the foot pushes off and moves forward to slow, weak force development to push-off the foot [21,22]. Short steps
execute the rst step. Relevant parameters for gait initiation may also reect imbalance as it is associated with higher double
include the duration and amplitude of the APA, push-off forces, and support time, i.e. both feet are on the ground for a longer proportion of
rst step length and latency of foot-off. the step cycle. Short steps may thus reect an inability to control body
A third component of walking ability, turning, requires even CoM on one leg during a long step. Patients with PD are capable of
more cognitive control to modify the gait pattern, execute an modulating cadence, thereby at least partly compensating for small
asymmetrical stepping pattern, and regulate dynamic balance [12]. step length [20,23]. In the upper body, bradykinesia is expressed by
In daily life, people make as many as 80e100 turns each hour, and reduced arm swing amplitude and velocity, particularly in the most
patients with PD make just as many turns as control subjects [13]. affected arm, and decreased range of motion of the trunk [4,24].
The stepping pattern during turning involves asymmetric rotation In addition to bradykinesia of gait, PD gait is characterized by
of the foot in space and of the upper body over the leg on the postural instability. Postural instability during gait can be observed
ground. Healthy adults turn by rst turning their eyes, then head, in larger step-to-step variability compared to healthy subjects
towards the new direction, followed by the trunk, pelvis and legs [1,25]. For example, the duration, length, and width of steps vary
[14]. The number of steps taken to complete the turn, speed of more over multiple steps in people with PD than their healthy
turning, dynamic postural stability (i.e. relation of the body center peers. This variability is believed to be related to increased fall risk
of mass (CoM) to the edge of foot support) and coordination of in PD [26,27], although this could not be conrmed in a large
head-trunk-feet motion are used to quantify turning [15]. prospective study in PD [28].
A fourth component of everyday gait is the ability to adjust gait to
negotiate environmental hazards, such as irregular surfaces and 2.2. Gait initiation
crowded spaces. This form of gait is highly dependent on cognitive
control to plan, make judgments, and inhibit actions [16e18]. Subjects with PD show hypometric APAs when initiating a step.
Adaptability of gait can be tested using obstacle avoidance paradigms, They produce less force, resulting in a smaller weight shift forward
K. Smulders et al. / Parkinsonism and Related Disorders 31 (2016) 3e13 5

and toward the stance leg than would be required for taking a step can partly be improved by levodopa, dopamine agonists, or in-
[21,29]. This reduction in push-off force causes a delay in step hibitors of dopamine metabolism. In this section, we discuss which
execution [21,30]. Moreover, the length of the rst step is shorter specic gait components and parameters are sensitive to dopami-
than in healthy elderly subjects [29,31e33]. In contrast to healthy nergic interventions. We limit this section to studies using motion
people, people with PD do not scale the APA size in proportion to analysis systems or wearable sensors, i.e. objective measures to
their stance width [33]. Unlike the spatial control of APAs, the assess gait.
relative timing (coordination of the movement pattern) is unaf- Note that almost all of the studies reviewed in this section have
fected by PD [30]. evaluated only short-term differences between on and off levo-
dopa states. Typically, subjects were tested at baseline, after >12 h
2.3. Turning of withdrawal of all dopaminergic medication, and tested again on
the same day about an hour after taking their medication. Only two
The sequential eyes-head-trunk-feet movement observed dur- studies compared the effect of dopaminergic treatment over pla-
ing turning in healthy adults is lost in PD patients; they turn en cebo [23,57], and only two out of nine studies counterbalanced on-
bloc, with a more simultaneous onset of eyes, head, trunk and leg off and off-on order (Table 1) [57,58]. All studies are based on
movement [34e37]. Speed of turning in people with PD is related to effects of monotherapy or combination therapy of levodopa and/or
axial tone in the neck, but not trunk or hips [38]. In addition, DA agonists, amantadine, MAO-I, or COMT inhibitors, dependent on
turning in people with PD is characterized by slow, jerky turning individual use.
and additional steps are needed to complete the turn [39e41].
When people with PD are asked to turn quickly, they become un-
stable as they spend more time than control subjects with their 3.1. Straight walking (Table 1)
body CoM outside their base of foot support [15].
Similar to improvements in other measures of bradykinesia, gait
2.4. Gait adaptability parameters that are related to movement amplitude and speed
benet from dopaminergic treatment. For example, increases in the
Problems stepping over an obstacle while walking are apparent amplitude of the movements of the legs, trunk and arms result in
in people with PD who have moderate (Hoehn & Yahr 2-3) disease larger step length, trunk motions, arm swing [24], and faster stride
severity [42e44]. People with PD have a higher number of obstacle velocity [59e62]. In contrast to spatial gait metrics, temporal
hits compared to healthy subjects [44,45]. During obstacle crossing, metrics are not improved as much by levodopa (Fig. 2). Cadence
people with PD are less stable than healthy subjects, reected in improves to a lesser extent [59], or not at all [61]. There is no evi-
more mediolateral movement of the CoM [46]. In addition, break- dence for decrease in double support time, which might be ex-
down in motor planning can result in riskier situations. For pected if levodopa reduced imbalance. However, and contrary to
example, the time needed to step over the obstacle is longer, the evidence above, one study suggests that variability of step time,
resulting in more time spent standing on one leg [44,47]. Also, the stride length, and gait speed can improve with dopaminergic
typical foot placement relative to the obstacle is smaller in PD pa- treatment [61]. Some evidence also suggests that asymmetry of
tients than in healthy subjects, increasing the risk of collision arm swing movements benet from dopaminergic therapy [24].
[42,44,45].
3.2. Gait initiation (Table 2)
2.5. Freezing of gait
Levodopa can improve the hypometria of the preparatory
A majority of people with PD eventually develop freezing of gait
stepping phases. Force generation for push off increases, resulting
(FoG) e the subjective feeling that the feet are glued to the ground
in higher amplitudes of the postural preparation phase (APA
e during the course of the disease [48]. Even without a freezing
[21,33,59]) and larger rst steps [33]. In contrast, neither the
event, patients prone to FoG show differences in gait parameters
duration of the APA, nor the size of the rst step was signicantly
compared to PD patients who do not freeze. People with PD and
improved by levodopa in the study of Curtze et al. [59] (Fig. 2).
FoG walk more slowly with shorter stride lengths than non-
freezers [49,50], which could be due to more advanced disease
stage in FoG [7]. Nevertheless, FoG has been associated with greater 3.3. Turning (Table 2)
spatial stride-to-stride variability [50,51], more time spent in
double support phase [49,52], and increased asymmetry between Whereas turning in place does not seem to benet from dopa-
the right and left legs [52]. During turning, subjects with PD who minergic treatment [38,63], making a turn to change walking di-
have FoG require more time to turn and have a smaller step width rection does. Turning speed and number of steps to complete the
than those without FoG [53]. turn improved with levodopa [38,59], but to a lesser extent than
All abovementioned aspects of gait impairments typically call parameters of straight walking [59] (Fig. 2). Interestingly, some
for more attentional control of walking [54]. A loss of automaticity evidence suggested that only patients with dyskinesia improved
of gait can be reected in more deterioration of gait while per- turning speed on dopaminergic medication [59].
forming a secondary task (dual task cost). In people with PD,
increased dual task costs in comparison to age-matched control
subjects are most prominent in gait stability measures, and in 3.4. Gait adaptability (Table 2)
people with more severe gait impairments, such as FoG [1,55,56].
Two studies evaluated the effect of dopaminergic treatment on
3. Effects of dopaminergic treatment gait adaptability. The ability to step over an obstacle during walking
improved when using dopaminergic medication [45]. Success rates
Pharmacological treatment aiming to increase the dopamine at avoiding obstacles changed in the ON state, with shorter and
neurotransmitter is most effective for bradykinesia, rigidity and faster steps to cross the obstacle, suggestive of less cautious
tremor. Although less effective for postural instability and falls, gait behavior [45,64].
6 K. Smulders et al. / Parkinsonism and Related Disorders 31 (2016) 3e13

Table 1
Overview of studies evaluating effects of dopaminergic treatment (On vs. Off) using quantitative measures during straight walking.

Fig. 2. A summary of the relative effects of taking levodopa on a wide variety of gait parameters during straight walking, gait initiation, and turning in a study of 100 people with
PD. This study is an example of how upper and lower body bradykinetic aspects of gait improve with levodopa, whereas measures related to stability of gait (such as double support
time) did not. The standardized response mean reects the size of the improvement with levodopa and is calculated as the mean score change divided by the standard deviation of
the score change. Adapted from C. Curtze, J.G. Nutt, P. Carlson-Kuhta, M. Mancini, F.B. Horak, Levodopa Is a Double-Edged Sword for Balance and Gait in People With Parkinson's
Disease, Mov Disord (2015). Copyright 2015 by the John Wiley & Sons, Inc. Adapted with permission.
K. Smulders et al. / Parkinsonism and Related Disorders 31 (2016) 3e13 7

Table 2
Overview of studies evaluating effects of dopaminergic treatment (On vs. Off) using quantitative measures for gait initiation, turning and gait adaptability.

3.5. Freezing of gait the gait item of the UPDRS-III than placebo or levodopa alone [74].
Together, these studies suggest that dopamine agonists augment
In most patients with PD and FoG, FoG episodes are more the effects of levodopa in advanced PD.
frequent, and last longer, when they are off dopaminergic medi-
cation compared to the on state [51,65,66]. In sharp contrast, a 4.2. Catechol-O-Methyl transferase (COMT) inhibitors
small group of people with PD have FoG that is induced by levodopa
[67]. The ELLDOPA trial showed that FOG severity could be reduced The effects of COMT inhibitors (entacapone, tolcapone) are
or delayed when on dopaminergic treatment [68]. However, there similar to DA agonists, extending the effects of levodopa therapy.
is very limited evidence that administration of levodopa and other COMT inhibitors inhibit the methylation of levodopa, thereby
dopaminergic agents can ameliorate stride length and stride time increasing the concentration of levodopa that enters the brain. As
variability in FoG to levels approaching non-freezers ([52,65,69]). such, COMT inhibitors, in conjunction with levodopa, are recom-
mended to decrease the amount of OFF time. Only two small
4. Effects of other antiparkinsonian drugs studies looked at the effects of COMT inhibitors on gait parameters,
providing support for tolcapone as an effective add-on to levodopa
In this section, we will summarize the effects of anti- to prolong benecial effects on gait speed [75,76].
parkinsonian drugs other than levodopa on gait, mostly as adjuncts
to levodopa treatment (Table 3). In contrast to studies focusing on 4.3. Monoamine oxidase type B inhibitors (MAOB-I)
levodopa, studies evaluating drugs other than levodopa are pri-
marily clinical trials in which gait was most commonly assessed MAOB inhibitors (selegiline and rasagiline) have been evaluated
using subjective measures. in people recently diagnosed with PD, in two large-scale studies, with
the aim to modify disease progression: DATATOP [77] and ADAGIO
4.1. Dopamine agonists [78]. Although gait was not an outcome in the original study, results
from a follow-up study suggested that PD patients on MAOB-I were
Dopamine D2 agonists are commonly used in PD, either as less likely to develop FoG [79,80] and had less increase of PIGD scores
monotherapy in early PD, or to reduce levodopa dose needed in over a period of 36 weeks [81]. These ndings were in line with
more advanced disease stages [70]. The specic effect of dopamine earlier work showing marginally faster gait speed in PD subjects on
agonists as monotherapy has been evaluated in an open-label un- MAOB-I compared to placebo [82]. However, a more recent, retro-
controlled study with previously-untreated subjects with PD. In spective study could not replicate a benecial long-term effect of
this study, six month use of the transdermal patch rotigotine MAOB-I on FoG or fall risk [83]. In addition, clinical lore suggests that
improved all aspects of gait compared to baseline, including addition of a MAOB-I to a patient developing FoG does not reduce the
straight walking, gait initiation and turning [71]. symptom. Future work to evaluate the effects of MAOB-I could
The additional value of DA agonists as an adjunct to levodopa benet from the use of more objective and sensitive measures of gait.
has been evaluated in three studies. Two studies found benecial,
immediate effects on gait speed of the DA agonist apomorphine 4.4. Amantadine
(sublingual) and pramipexole compared to levodopa alone [72,73].
In a large-scale, placebo-controlled study, the long-term effect of Amantadine, an older antiviral agent, is a glutamate antagonist
pergolide, in combination with levodopa, yielded better effects on recommended for the treatment of dyskinesia in PD [70]. Recently,
Table 3
Description of studies evaluating medication effects (other than levodopa) on gait and/or falls in PD.

Authors Drug Subjects Study design Time Objective (O) / Effect on gait Effect on
(mean) Subjective (S) falls
Assessment

Dopamine Agonists [71] Rotigotine PD untreated (n 24) Uncontrolled study 6 months O Improves all gait
aspects
[73] Pramipexole PD with dyskinesia/ Double-blind, placebo- Immediate O Increases walking
uctuations (n 13) controlled, cross-over study. speed
[72] Apomorphine PD with dyskinesia/ Double-blind, placebo- Immediate O Increases walking
(sublingual) uctuations (n 10) controlled study speed
[74] Pergolide PD with dyskinesia/ Double-blind, placebo- 6 months S Improves gait
wearing off (N 367) controlled study. (UPDRS)
COMT Inhibitors [76] Tolcapone with PD with uctuations Double-blind, placebo- Immediate O No effect on gait
apomorphine (n 5) controlled, cross-over study. speed
(sublingual)
[75] Tolcapone with PD (n 7) Uncontrolled study Immediate O Improved gait
levodopa and 6 speed
weeks
Monoamine oxidase [81] Rasagiline PD untreated (n 392) Double-blind, placebo- 36e72 S Less increase in
type B inhibitor controlled, delayed start weeks PIGD over time
(MAOB-I) study.
[83] MAOB-I PD (n 302) Retrospective, cross-sectional 12 months S No effect on FoG No effect
(grouped) study (minimal)
[79] Selegiline PD de novo (n 368) Double-blind, placebo- 14 months S Less FoG
[80] controlled study
[82] Selegiline PD with uctuations Double-blind, cross-over trial 3 weeks O Higher gait speed
(n 16)
Amantadine [85] Amantadine PD with FoG (n 40) Double-blind placebo 5 days S No effect on
controlled study primary FoG
outcome
[87] Amantadine PD patients with STN-DBS Uncontrolled study 10 months S Improves gait item
and incomplete axial UPDRS-III
benet (n 46)
[86] Amantadine PD with FoG (n 8) Double-blind placebo 2 days S+O No improved gait
controlled study. speed over placebo
[84] Amantadine PD with FoG (n 11) Self-reports, no controlled 20 months S Improves FoG
conditions.
Glutamatergic [89] Memantine PD with severe gait Double-blind, placebo- 90 days S+O No improvement
agents (adjunct) disability (n 25) controlled.
Cholinergic agents [102] Rivastigmine PD moderate severity Double-blind, placebo- 32 weeks O Improved gait Improved
(n 114) controlled trial (speed and
variability)
[98] Donepezil PD with recurrent falls Double-blind study, placebo- 6 weeks S Improved
(n 23) controlled, crossover trial
[136] Galantamine PD with dementia Open-label, randomized 24 weeks S Improved Improved
(n 41) controlled trial.
Norepinephrinergic [108] Droxidopa PD with neurogenic Placebo-controlled, double- 15 days S Inconclusive
agents orthostatic hypotension blind randomized trial.
(n 147 over 2 groups)
[106] Droxidopa with PD with FoG (n 18 over Uncontrolled, open-label. 4 weeks S Combination
entacapone 3 groups) lessens FoG
severity
[105] Droxidopa PD with FoG (n 11) Uncontrolled, open-label. Not S No overall effect
reported
[104] Droxidopa PD with FoG (n 9) Uncontrolled, open-label. Not S Improves FoG
reported
Methylphenidate [113] Methylphenidate PD with STN DBS (n 12) Double-blind, placebo- 3 months O No effects on gait
controlled trial hypokinesia
[89] Methylphenidate PD with STN DBS (n 65) Double-blind placebo- 90 days O OFF state:
controlled trial. improved speed,
FoG less
ON state: gait not
improved, FoG
improved
[114] Methylphenidate PD (n 17) Double-blind placebo 12 weeks O OFF state: slight
controlled trial. Composite gait improvement
score of gait, initiation, ON state: no
turning improvements
[112] Methylphenidate PD advanced, with STN Uncontrolled. 3 months S+O Stand-walk-sit
DBS (n 17) improved. Less FoG
[111] Methylphenidate PD (n 17) Double-blind, placebo- Immediate O Improves TUG
controlled trial speed in
combination with
levodopa
[110] Methylphenidate PD (n 21) Single dose, open-label Immediate O Improves TUG and
gait (speed and
variability)

Abbreviations: PIGD: postural instability and gait difculty; FoG: Freezing of Gait; STN DBS: Deep brain stimulation of the subthalamic nucleus.
K. Smulders et al. / Parkinsonism and Related Disorders 31 (2016) 3e13 9

amantadine has been tested for its potential ameliorative effect on label, uncontrolled studies reported conicting results on FoG
FoG in PD. Although there was initially some promise for short- through L-DOPS administration [104,105]. More recently, the a
term benets for FoG from an uncontrolled trial [84], two double- study on the effect of L-DOPS in combination with a COMT inhibitor
blind studies failed to see improvement of FoG in people with PD found that self-reported FoG was alleviated in the group taking L-
after several days of amantadine use when compared with placebo DOPS and entacapone, whereas this effect was absent the groups
[85,86]. However, a double-blind, placebo-controlled study re- on L-DOPS or entacapone alone [106].
ported some improvements on secondary outcome measures of Another norepinephrine agent, droxidopa, has been reported to
FoG, such as whether or not subjects reported FoG on a question- improve neurogenic orthostatic hypotension in PD [107]. Recent
naire [85]. In addition, amantadine has been tested for PD patients evidence suggests that normalizing orthostatic hypotension in PD
with axial impairments after STN-DBS surgery [87]. This uncon- subjects reduces the risk for falls [108]. No studies have evaluated
trolled study reported improvement on the gait item of the UPDRS- the effects of norephinephrine agents on objective measures of gait.
III. To conclude, more long-term and well-controlled studies are
needed to conrm a potential effect of amantadine on objective gait 5.4. Methylphenidate
measures.
The effect of methylphenidate is commonly used in attention-
5. Effects of other classes of medication decit disorders to enhance attention functions, acting primarily
as a dopamine reuptake inhibitor [109]. In combination with
In this section, we will describe effects of drugs other than levodopa, methylphenidate improved immediate levodopa effects
dopaminergic agents that are less commonly used to treat on gait speed [110,111] and temporal variability of gait [110] in
parkinsonian symptoms, or might be used for co-morbidities. people with PD. More recently, methylphenidate has been used in
Table 3 summarizes these studies. more advanced PD patients with treatment-resistant FoG after
STN-DBS. A multi-center RCT reported improvements in FoG in
5.1. Glutamatergic agents these advanced patients [89], in line with previous non-RCT studies
[110,112]. However, using more specic measurements of gait in a
Apart from amantadine, memantine is a glutamate agent acting small sample (n 12) in the same study did not provide evidence
as N-methyl-D-aspartic-acid-related (NMDA) receptor antagonists for improvement [113]. In subjects with PD with moderate gait
that has shown promising gait benets in demented subjects [88]. impairments (no DBS), no benecial effects of methylphenidate
There is one (phase I) study in PD evaluating the use memantine as could be demonstrated, although the authors reported some slight
adjunct-therapy to levodopa in patients with severe gait and bal- improvements on methylphenidate in a gait composite score when
ance impairments [89]. This pilot study did not report improve- off, but not when on dopaminergic treatment [114]. In summary,
ments in gait speed or stride length in the group on memantine there is inconclusive evidence for a benet of methylphenidate to
compared to placebo. However, axial signs as assessed in the improve gait function in PD.
UPDRS-III did show some improvement.
6. Effects of drugs for co-morbidities
5.2. Cholinergic agents
Different classes of drugs are known to increase fall risk in
Recent research has highlighted the role of cholinergic activity elderly [115e117] and hospitalized people [118e121]. These drugs
in gait and balance impairments in PD [90e93]. Loss of cholinergic include anti-depressive, anti-psychotic, sedative/hypnotic, and
activity of the pedunculopontine nucleus (PPN) -thalamic tract in opiod analgesic agents. There is, however, a lack of research
PD has been related to fall risk [91,94], and reduced cholinergic investigating the effects of these classes of drugs on fall risk in
activity in the cortex associates with slower gait speed in people people with Parkinson's disease. Also, it is not well understood
with PD [90]. This could suggest that loss of cholinergic activity in what aspects of gait and balance these drugs worsen.
the cortex reduces gait speed through attentional loss, in line with Drugs with high sedative properties, including antipsychotics,
consistently reported associations between attention and gait pa- tricyclic anti-depressants, benzodiazepines and hypnotics, have
rameters [1,28,95,96]. found to result in lower gait speed in elderly [122]. It is likely that
Cholinergic treatment with cholinesterase inhibitors (ChE-I; for psychomotor slowing is a main driver of this effect. With regard to
example rivastigmine, donepezil) is commonly used for cognitive antidepressants, evidence suggests that effects on gait depend on
enhancement in patients with Alzheimer's disease (AD), and has the specic type of prescribed medication. For example, there is
also shown efcacy in patients with Parkinson's disease dementia interesting work on the impact of anti-depressants on obstacle
[97]. Preliminary ndings suggested that ChE-I can reduce falls in avoidance performance in elderly, showing that tricyclic antide-
people with PD at high risk for falling [98] and improve gait in AD pressants (here amitriptyline), but not paroxetine, deteriorates gait
[99e101], potentially through improving attention. A recent, large adaptability [123,124].
double-blind, placebo-controlled trial (RESPOND trial [102]) eval- Another class of drugs that may cause gait impairments and
uating gait variability and, secondarily, fall risk provided additional increase fall risk are anti-hypertensives. Particularly diuretics and
support for the benecial effects of rivastigmine on gait for PD angiotensin system modiers seem to increase fall risk in elderly
patients at risk for falls. Another phase II study is currently un- populations [115,118]. There is some pilot work in PD suggesting
derway to establish the effect of donepezil on gait, postural stability that correcting hypotension in patients with PD (systolic blood
and fall risk in PD, and evaluate its effect on attentional demands of pressure > 80 during standing for all subjects) leads to improved
gait [103]. gait, reected in higher gait velocity [125].
Drugs with anticholinergic properties are commonly used in PD
5.3. Norephinephrine agents for hyperactive bladder, treatment of tremor and depression. Apart
from detrimental effects on cognition, these agents are associated
In the early 1980s, a number of studies in Japan were conducted with lower gait speed in elderly [126] and with increased fall risk in
to evaluate the effect of L-threo-3,4-dihydroxyphenylserine (L- psychiatric inpatients [127]. As yet, no studies in PD subjects have
DOPS), a precursor of norepinephrine, on FoG in PD. Two open- been carried out.
10 K. Smulders et al. / Parkinsonism and Related Disorders 31 (2016) 3e13

Although not a prescribed medication, the care provider should of daily life than the commonly used, straight, non-obstructed walk
always be aware of alcohol as an acute and chronic cause for gait through the clinic hallway. As put forward in the Introduction, pa-
disturbances and falls [128,129]. tients with PD have considerable difculty with the initiation,
turning and adaptability components of walking. These components
7. Summary and future perspectives have largely been neglected in research studies. Recent studies have
introduced cognitively demanding secondary tasks while walking to
In summary, bradykinetic and hypometric spatial characteristics assess attentional demands of walking [102,134,135]. Another op-
of gait and turning improve with dopaminergic medication. How- tion would be to assess obstacle avoidance skills. Lastly, laboratory-
ever, it is unclear whether more complex walking skills, such as gait based studies to better understand the pharmacological effects on
initiation and gait adjustments, improve with dopaminergic gait, in a mechanistic fashion, could be improved by introducing
treatment. Dopaminergic treatment effects on stability measures of placebo-controlled designs and account for order biases by
gait, such as spatial or temporal variability, are thus far inconclu- randomizing the order of on-off assessments.
sive. Dopamine agonists, MAOB and COMT inhibitors as adjunctive
therapy to levodopa are most likely to improve or prolong the ef- Contributor's roles
fects of levodopa, hence improving bradykinesia and hypometria in
gait. Although there is some evidence for a benecial effect of Conception of review: KS, FBH, JGN. Writing of rst draft: KS,
amantadine on freezing of gait, most work yields inconclusive MLD. Review and critique: PCK, MLD, JGN, FBH.
results.
Gait stability and balance have long been considered to be Funding source
insensitive to levodopa treatment, encouraging research to look
into other neurotransmitter possibilities. Recent work shows This publication was made possible with support from grants
promising results for cholinesterase inhibitors to improve gait from the National Institutes of Health (AG006457-29; 2P50
variability and potentially reduce fall risk, in patients who are at NS062684), a VA Merit award (I01 RX001075-01), and the Medical
high risk for falls [98,102]. Whether these benets stem from Research Foundation of Oregon. These funding sources had no
increased cholinergic activity in the cortex, related to attention involvement in this study.
processes, or in the PPN e thalamic tracts is an unanswered,
important question. Improving gait through attention or cognitive
Conict of interest
control processes is a relatively new approach, opening up new
treatment avenues using cognition-enhancing drugs. Besides
Oregon Health & Science University and Dr. Horak have a sig-
cholinergic treatment, memantine has been considered for this
nicant nancial interest in APDM, a company that may have a
purpose. Although there is some efcacy evidence of memantine to
commercial interest in the results of this research and technology.
improve gait variability in demented people without PD [88], a pilot
This potential institutional and individual conict has been
study in PD failed to observe such effects [89].
reviewed and managed by OHSU. All other authors declare no
There is a paucity of literature on other, common drugs that can
conict of interest.
impair gait in people with PD, such as drugs with sedative, anti-
cholinergic or antihypertensive effects, known to increase fall risk
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